Scientists Find New Point of Attack on HIV for Vaccine Development

April 24, 2014

NEW YORK — Scientists from The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) have discovered a new vulnerable site on HIV that antibodies can attack to prevent infection from a broad range of the virus’ many variants.

“HIV has very few known sites of vulnerability, but in this work we’ve described a new one, and we expect it will be useful in developing a vaccine,” said Dennis R. Burton, professor in TSRI’s Department of Immunology and Microbial Science and scientific director of the IAVI Neutralizing Antibody Center (NAC) and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID).

“HIV mutates very quickly, within the individual and across populations,” said IAVI Chief Scientific Officer Wayne Koff. “This new target offers a stable mark for vaccine design, increasing the potential to find a vaccine that can provide broad, lasting protection to people around the world.”

The findings, reported in two studies published online today and in the May issue of Immunity, are part of a large effort sponsored by IAVI and the U.S. National Institutes of Health (NIH) to develop AIDS vaccines that can trigger the human immune system to produce broadly neutralizing antibodies (bNAbs). Since 2009, researchers have: determined that a small proportion of HIV-infected individuals naturally generate bNAbs against a wide range of HIV variants; isolated scores of these bNAbs; identified a handful of regions they target on HIV; and found they can prevent HIV infection in non-human primates. The next step is to design immunogens to elicit these bNAbs in humans.

In the first study, a team of scientists from TSRI, IAVI and Theraclone Sciences, led by Dr. Burton, identified and described a promising new set of bNAbs, the PGT151 series, building on the Protocol G project that studied HIV-infected people who naturally produce bNAbs. The researchers found that two of the antibodies in the series could block infection by more than two-thirds of HIV strains found in patients worldwide.

In the second study, a team led by Ian A. Wilson, TSRI Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology, explored the newly identified target, which becomes the fifth well-characterized epitope, or binding site, on the surface of HIV.

The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996, IAVI works with private companies, academics, and civil society partners in 25 countries to research, design, and develop AIDS vaccine candidates. In addition, IAVI conducts policy analyses and serves as an advocate for the AIDS vaccine field. IAVI supports a comprehensive approach to addressing HIV and AIDS that balances the expansion and strengthening of existing HIV-prevention and treatment programs with targeted investments in the design and development of new tools to prevent HIV. IAVI is dedicated to ensuring that a future AIDS vaccine will be available and accessible to all who need it.

IAVI’s work is made possible by generous support from many donors including: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org.

These studies were made possible in part by the generous support of the American people through USAID. USAID administers the U.S. foreign assistance program providing economic and humanitarian assistance in more than 120 countries worldwide. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.

About the two Immunity Papers

“Broadly Neutralizing HIV Antibodies Define a Novel Glycan-dependent Epitope on the Pre-fusion Confirmation of gp41 on cleaved Envelope trimers” (E. Falkowska, A. Ramos, K.J. Doores et al., Immunity, May 2014): Researchers found a set of eight closely related antibodies, the PGT151 series, in the blood samples of an HIV-positive donor. Laboratory tests showed that two, PGT151 and PGT152, could block infection by more than two-thirds of HIV strains found in patients worldwide. Unlike other bNAbs, which bind to specific subunits comprising the HIV trimer (“conserved” or stable sites on HIV’s surface envelope protein), PGT151 attaches to several different parts of the envelope protein. In fact, the binding site for PGT151 occurs only on mature and properly assembled trimer structures. This work expands upon the Protocol G project’s isolation and characterization of other bNAbs discovered by IAVI, The Scripps Research Institute and Theraclone Sciences using Theraclone’s I-STAR technology.

Funding for this study was provided by IAVI; the National Institutes for Health (grant AI33232, HIVRAD P01 AI82362); the NIH-funded Center for HIV / AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) (grant UM1AI100663); The Ragon Institute of Massachusetts General Hospital, MIT and Harvard; and the Aids Fonds Netherlands (grants #2011032, #2012041).

“Structural Delineation of a Quaternary, Cleavage-dependent Epitope at the gp41-gp120 interface on intact HIV-1 Env trimers” (C. Blattner, J.H. Lee, K. Sliepen, et al., Immunity, May 2014): Using electron microscopy and x-ray crystallography, researchers helped visualize the vulnerable binding site for the PGT151 series targeting gp41 and gp120, two subunits of the HIV envelope trimer. Specifically, researchers observed how PGT151 binds to one gp41 protein with two associated sugars (known as glycans), a patch on the gp120 protein and even a piece of adjacent gp41 within the trimer structure, a very complex epitope. Interestingly, PGT151 binding also stabilizes the trimer’s fragile structure—a key breakthrough that will help vaccine developers better understand the molecular structure of binding sites targeted by potential vaccines.

Funding for this study was provided by IAVI; CHAVI-ID (UM1 AI100663); NIH (P30AI036214, HIVRAD P01 AI082362 and R01 AI084817); the University of California, San Diego Center for AIDS Research; The California HIV / AIDS Research Program; Aids Fonds Netherlands (grant #2011032); the Netherlands Organization for Scientific Research; the European Research Council; and the German Academic Exchange Service.About Protocol G

In 2006, IAVI and its Neutralizing Antibody Consortium launched the Protocol G project to search for bNAbs against HIV, partnering with clinical research centers in Africa, India, Thailand, Australia, the United Kingdom, and the United States. More than 1,800 healthy, HIV-positive volunteers contributed blood samples to be screened. In 2009, scientists from IAVI, The Scripps Research Institute, and Theraclone Sciences collaborated to isolate and characterize the first new bNAbs to HIV seen in a decade and the first to be isolated from donors in developing countries, where the majority of new HIV infections occur. To date, more than 25 new bNAbs have been isolated and characterized from Protocol G specimens, and many have been shared with researchers across the AIDS vaccine field.

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

Theraclone is a biopharmaceutical company focused on the discovery and development of novel, monoclonal antibody therapeutics for diseases that are devastating for patients and their families and which are a significant threat to human health. Theraclone leverages its proprietary antibody discovery technology, I-STARTM (In-Situ Therapeutic Antibody Rescue), to identify rare fully human antibodies, from immunologically relevant human subjects, that may be developed into antibody product candidates that are potentially safer and more effective than current therapies, or that address an unmet need. With a primary focus on cancer and infectious disease Theraclone has a portfolio of innovative antibody programs at preclinical and clinical development stage targeting serious medical conditions with a significant unmet medical need.